For a tumor to grow large, blood vessels to deliver nutrition and oxygen to the tumor need to be increased depending on the growth of the tumor. Tumor cells are considered to induce angiogenesis of tumor blood vessels by secreting the vascular growth factor by themselves that stimulate the growth of vascular endothelial cells of neighboring blood vessels. Therefore, attempts have been made to treat or prevent tumor by inhibiting the function of vascular growth factors and suppressing tumor angiogenesis. As one of such methods, a vaccine therapy targeting tumor angiogenesis-related factors has been attracting attention. In the vaccine therapy, cancer is treated or prevented by administering a tumor angiogenesis-related factor, an epitope contained in the factor, or an expression vector encoding them to cancer patients or targets having a risk of developing cancer to induce an antibody against the tumor angiogenesis-related factor in the body of the patients, thereby neutralizing the function of the factor and suppressing tumor angiogenesis. As the tumor angiogenesis-related factor, various factors such as VEGF, angiopoietin, FGF, PDGF and the like are known.
For example, patent document 1 discloses a method of inhibiting vascular endothelial cell proliferation in a tumor microenvironment, preventing angiogenesis and inhibiting growth and metastasis of tumor, by administering a DNA vaccine encoding VEGF receptor-1, VEGF receptor-2 or Flk-1.
Patent document 2 describes suppression of angiogenesis-related diseases, particularly of the development and metastasis of cancer, by using heterologous VEGF vaccines.
However, the immune tolerance to factors such as VEGF and the like has generally been established since these factors are the patient's self components. Therefore, even when these factors or partial peptides thereof are directly administered to patients, it is difficult to efficiently induce antibodies to these factors in the body of the patients. As such, some technical idea is necessary to make the patients' immune system recognize these self-antigens, thereby inducing the production of the antibodies thereto.
Hepatitis B virus core (HBc) antigen protein constitutes spherical core particles by self-assembly. The core particles have very high immunogenicity. When a fusion polypeptide obtained by inserting a desired epitope into a particular site of the HBc antigen protein, or connecting a desired epitope to the terminus of the HBc antigen protein is used, the epitope is presented on the surface of the particles formed by self-assembly. Using the fusion polypeptide, the inserted epitope is easily recognized by the immune system, and the production of the antibody that recognizes the epitope can be efficiently induced. Therefore, utilizing the HBc antigen protein as a platform of vaccine, attempts have been made to induce production of the antibody even though an antigen is difficult to be recognized by the immune system (non-patent document 1, non-patent document 2).
Patent document 3 discloses particles composed of a chimeric HBc antigen protein containing an exogenous amino acid sequence having an epitope, wherein the exogenous amino acid sequence is inserted between the amino acid residues 80-81 of the HBc antigen.
However, the effectiveness of the vaccine for tumor angiogenesis-related factor is not sufficiently satisfactory.